We wish to better understand how nuclear hormone receptors participate in signal transduction in normal cells, and the lesions in this process that lead to disease. Nuclear hormone receptors are transcription factors that regulate gene expression in response to small lipophil ligands, such as steroids, thyroid hormones, and retinoids. Nuclear hormone receptors regulate key aspects of normal metazoan reproduction, proliferation, differentiation, and homeostasis; aberrant receptors are causal factors in a variety of human endocrine and neoplastic disorders. Many nuclear hormone receptors exhibit bimodal transcriptional properties, and can either repress or activate gene expression. Transcriptional repression is least understood of these effects. Recently, we and other have identified a family of "co-repressors" (variously detonated TRACs, SMRT, N-CoR, or RIP13) that physically associate with nuclear hormone receptors and appear necessary for transcriptional silencing by these receptors. Our primary goal is to determine the roles of these co- repressors in receptor-mediated gene regulation. Specifically: 1. We will determine how co-repressors interact with receptors, and the manner in which the interaction is regulated. 2. We will determine how co-repressors interaction with other regulatory pathways that are know to modulate receptor function. 3. We will also elucidate how co-repressors, together with the receptor itself, interact with the transcriptional machinery and with chromatin to mediate transcriptional silencing. 4. We will determine the roles co-repressors play in human endocrine and neoplastic disorders. As a secondary goal we will also characterize an additional series of potentially novel effectors and/or modulators of nuclear hormone receptor action that we have recently identified. The results from these experiments will contribute to our understanding of the molecular basis behind hormone receptor function in both the normal and the diseased organism.